Pelizaeus-Merzbacher-like disease caused by AIMP1/p43 homozygous mutation

Abstract

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by PLP1 mutations. A similar autosomal-recessive phenotype, Pelizaeus-Merzbacher-like disease (PMLD), has been shown to be caused by homozygous mutations in GJC2 or HSPD1. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD in which linkage to PLP1, GJC2, and HSPD1 was excluded. Through genome-wide homozygosity mapping and mutation analysis, we demonstrated in all affected individuals a homozygous frameshift mutation that fully abrogates the main active domain of AIMP1, encoding ARS-interacting multifunctional protein 1. The mutation fully segregates with the disease-associated phenotype and was not found in 250 Bedouin controls. Our findings are in line with the previously demonstrated inability of mutant mice lacking the AIMP1/p43 ortholog to maintain axon integrity in the central and peripheral neural system.

Figure 1

Pedigree of the Affected Israeli Bedouin Kindred (A and B) The pedigree is compatible with autosomal-recessive heredity. (A) and (B) are branches of a single extended tribe, remotely related (not first or second degree).

Figure 2

MRI of Two Affected Individuals (A–C) Girl age 5 years with severe form of PMLD. The images demonstrate arrested myelination and reduced N-acetylaspartate. The T2-weighted images showed high signal of hypomyelination starting at a normal stage (A), as well as high signal on flair (B). Magnetic resonance spectroscopy demonstrated relative decrease of N-acetylaspartate within the white matter, likely because of axonal degeneration (C). (D–F) Girl age 14 months with severe form of PMLD. The images demonstrate incomplete myelination and corpus callosum atrophy. These findings were seen as low signal on T1-weighted images (D). On diffusion-weighted images, eADC showed low signal (E) representing increased diffusivity secondary to hypomyelinated brain tissue. Generalized brain atrophy, especially of the corpus callosum, was noted (F).

Figure 3

Fine Mapping of the 4q24 Locus in Kindred 1 and Kindred 2 (A) Disease-associated haplotype shown in boxes. Markers D4S2634 and chr4:107336226-107336269 define the minimal homozygosity locus associated with the disease. Blank spaces indicate nongenotyped markers. (B) Schematic presentation of the defined locus and the genes it contains (UCSC). Markers within the homozygosity locus are boxed.

Figure 4

The c.292_293delCA Mutation in Exon 4 of AIMP1 (A–C) Sequence analysis is shown for an unaffected individual (A), an obligatory carrier (B), and an affected individual (C). (D) SMART display of human AIMP1 domains along the wild-type sequence versus the mutant protein. The aberrant region in the mutant protein includes the tRNA-binding domain, a sequence needed for interaction with HSP90B1, and a region required for endothelial cell death and migration. The protein sequence is altered after 97 aa, and a stop codon truncates the protein after 127 aa. (E) Conservation of AIMP1 domains throughout evolution. Deleted area is boxed.